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Herpes Simplex Virus (HSV) as a Cause of Vesicobullous Lesions

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1. INTRODUCTION

• HSV-1: Primarily responsible for orofacial and labial lesions
• HSV-2: Primarily responsible for genital lesions, though either type can infect either site

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2. VIROLOGY & STRUCTURE

• gB and gD: Mediate viral attachment and fusion with host cell
• gC: Binds complement component C3b (immune evasion)
• gE: Acts as IgG Fc receptor (immune evasion)
• gG: Determines type-specific serology (gG-1 for HSV-1, gG-2 for HSV-2)

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3. PATHOGENESIS - HOW THE VESICLE FORMS

3a. Primary Infection

1. Inoculation: Virus enters through abraded skin or mucous membrane via direct contact
2. Local replication: The virus replicates in keratinocytes of the epidermis and dermis
3. Cytopathic effects: The infected keratinocytes undergo:
   • Ballooning degeneration - cells swell due to intracellular edema
   • Acantholysis - loss of intercellular adhesion
   • Reticular degeneration - the cell cytoplasm collapses into a network
4. Vesicle formation: Separation of necrotic keratinocytes from each other and from the basal layer creates an intraepidermal vesicle filled with serous fluid, free-floating virally-infected keratinocytes, and inflammatory cells
5. Neurotropism: The virus then enters local sensory nerve terminals and ascends by retrograde axonal transport to the dorsal root ganglia or trigeminal ganglia, where it establishes latency

3b. Latency

• Viral DNA persists as a circular episome within neuronal nuclei
• No viral proteins are expressed except Latency Associated Transcripts (LATs)
• The virus is "hidden" from immune surveillance
• Latency is maintained by HSV-specific CD8+ T lymphocytes that cluster around latently infected neurons

3c. Reactivation

• Emotional stress, UV light (sunlight), fever, menstruation, trauma, fatigue, immunosuppression
• The virus reactivates, undergoes anterograde transport down the axon, and re-infects the skin at or near the original site, producing recurrent vesicobullous lesions

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4. HISTOPATHOLOGY - THE BASIS OF VESICLE FORMATION

• Intraepidermal vesicle: The vesicle is located within the epidermis (as opposed to subepidermal in bullous pemphigoid)
• Ballooning degeneration: Infected keratinocytes are greatly enlarged with pale, "ballooned" cytoplasm and marginated chromatin
• Reticular degeneration: Fluid accumulates within the cytoplasm, rupturing cell walls into a network
• Multinucleated giant cells (Tzanck cells): Fusion of adjacent infected keratinocytes under viral glycoprotein mediation produces large cells with 2-8+ nuclei arranged in a "grape-like" cluster with "nuclear molding" and ground-glass chromatin
• Cowdry Type A intranuclear inclusion bodies: Eosinophilic intranuclear inclusions surrounded by a clear halo (pathognomonic)
• Acantholysis: Loss of intercellular bridges secondary to reticular degeneration
• Dermal inflammatory infiltrate: Lymphocytes and histiocytes in the dermis

The vesicle is intraepithelial and filled with serum and free-floating, virally infected keratinocytes and inflammatory cells. (Cummings Otolaryngology, Chapter 87)

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5. CLINICAL PRESENTATIONS OF HSV VESICOBULLOUS LESIONS

5a. Herpes Labialis (Cold Sore / Fever Blister) - Most Common

1. Prodrome: Tingling, burning, pruritus, or pain at the site (precedes lesions by 45-60% of episodes, lasting up to 48 hours)
2. Erythema and papule: Area becomes erythematous; grouped papules appear
3. Vesicle: Classic thin-walled, grouped vesicles on an erythematous base - this is the "vesicular stage"
4. Ulcer/Erosion: Vesicles rupture to form shallow, painful ulcers/erosions
5. Crust: A honey-colored crust forms; heals without scarring in 5-15 days

5b. Primary Herpetic Gingivostomatitis

• Classic primary infection presentation in children (HSV-1)
• Prodrome: Fever, malaise, myalgia, cervical lymphadenopathy
• Lesions: Clusters of small thin-walled vesicles on both keratinized (hard palate, gingiva) and non-keratinized (buccal mucosa, tongue) surfaces
• Key feature: Gingival involvement with erythematous, boggy, tender gingiva with free gingival margin involvement - a key diagnostic criterion
• Vesicles are short-lived on mucosa, rapidly rupturing to form shallow, painful ulcers
• Duration: 7-14 days; viral shedding continues for weeks after clinical resolution

5c. Genital Herpes

• HSV-2 (predominantly) or HSV-1
• Primary episode: Multiple grouped vesicles on erythematous base on the penis, vulva, vagina, cervix, or perineum; accompanied by fever, dysuria, inguinal lymphadenopathy. Vesicles rapidly ulcerate. More severe and prolonged than recurrences.
• Recurrent episodes: A prodrome of tingling/burning precedes 1-3 grouped vesicles that ulcerate and heal within 5-10 days. Recurrences are less severe than primary episodes.

5d. Herpetic Whitlow

• HSV infection of the distal finger (usually from autoinoculation via oral herpetic infections in children; occupational in healthcare workers from patients' oral secretions)
• Presents as grouped vesicles with deep pain and erythema of the fingertip
• Can mimic bacterial paronychia but is NOT fluctuant and should not be incised

5e. Eczema Herpeticum (Kaposi Varicelliform Eruption - KVE)

• Widespread dissemination of HSV over skin with a pre-existing skin disorder (most commonly atopic dermatitis, also pemphigus, burns, Darier disease, cutaneous T-cell lymphoma)
• Mechanism: Impaired epidermal barrier + Th2 immune shift + decreased antimicrobial peptides
• Lesions: Hundreds of umbilicated vesicles arising acutely over eczematous areas, with fever and regional lymphadenopathy
• In severely immunocompromised patients (pemphigus + systemic immunosuppression), can be fatal from S. aureus septicemia or visceral dissemination
• Risk factors include: severe atopic dermatitis, high IgE, eosinophilia, age of AD onset <5 years, use of topical calcineurin inhibitors

5f. Herpes Gladiatorum

• Grouped vesicles and erosions on the neck, face, and arms of wrestlers and rugby players (direct skin-to-skin contact)
• Caused by HSV-1

5g. Neonatal Herpes

1. Skin, eye, mouth (SEM) disease: Vesicles on skin (often on the presenting part), eye lesions, oral vesicles - best prognosis
2. Encephalitis: Seizures, lethargy, bulging fontanel - mortality 64% with treatment; only ~30% develop normally
3. Disseminated disease: Multi-organ failure with hepatitis, pneumonitis, DIC; mortality 30% with treatment

• Important: >20% of neonates with neurologic and disseminated disease do NOT develop cutaneous vesicles
• Transmitted primarily from maternal genital infection at delivery; primary maternal HSV carries 25-50% transmission risk; recurrent maternal HSV <3% risk

5h. HSV in Immunocompromised Patients

• Frequency of recurrences increases
• Vesicles evolve into chronic, extensive, deep, painful ulcers (perianal region, genitalia, tongue are favored)
• Atypical presentations: folliculitis, verrucous plaques, hypertrophic anogenital masses simulating neoplasia
• Can disseminate to viscera (esophagitis, pneumonitis, hepatitis, encephalitis)
• Acyclovir resistance (usually due to thymidine kinase mutation) more common (~5% vs ~1% in immunocompetent)

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6. IMMUNOLOGY

Innate Immunity

• Keratinocytes express Toll-like receptors (TLR-2, TLR-9) that detect HSV
• TLR signaling induces Type I interferons (IFN-α/β), which inhibit viral mRNA translation and promote NK cell activation
• NK cells kill infected cells via perforin/granzyme and release IFN-γ
• Langerhans cells in the epidermis are important antigen-presenting cells

Adaptive Immunity

• CD8+ T cells are the primary defense - they kill infected cells through perforin and Fas pathways
• CD4+ T cells release IFN-γ, recruit CD8+ cells, and help B cells produce antibodies
• Humoral immunity: Antibodies reduce virus titers at inoculation sites; maternal IgG protects neonates

HSV Immune Evasion

• ICP47 protein: Binds TAP (Transporter associated with Antigen Processing), blocking MHC class I peptide loading - infected cells "hide" from CD8+ T cells
• gC: Binds complement C3b, blocking complement activation
• gE: Functions as IgG Fc receptor, blocking antibody-dependent cellular cytotoxicity
• VHS (Virion Host Shutoff) protein: Degrades host mRNA, prevents DC activation
• HSV decreases langerin expression and increases apoptosis of Langerhans cells

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7. DIAGNOSIS

Clinical Diagnosis

• Characteristic grouped vesicles on an erythematous base, often with prodromal symptoms
• History of recurrence at same site is strongly suggestive

Laboratory Methods

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8. DIFFERENTIAL DIAGNOSIS OF VESICOBULLOUS LESIONS

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9. HSV AND ERYTHEMA MULTIFORME

• Recurrent HSV infection is the most common precipitating event in recurrent erythema multiforme (EM)
• The pathogenesis is immunological (not direct viral lesions at the EM site) - HSV DNA fragments are found in EM lesions, triggering a CD4+ Th1 immune response
• Lesions: symmetric, acral distribution; target lesions on elbows, knees, face, nailfolds
• Mild mucosal involvement (mouth only)
• Self-limited, lasts ~3 weeks; heals without scarring
• Treatment: Suppressive acyclovir reduces recurrent HSV-triggered EM episodes

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10. TREATMENT

Antiviral Agents (Mechanism: Inhibit viral DNA polymerase)

• Acyclovir is a guanosine analogue prodrug
• Monophosphorylated by viral thymidine kinase (TK) - highly selective for infected cells
• Then further phosphorylated by cellular kinases to acyclovir triphosphate
• Inhibits viral DNA polymerase and causes chain termination
• Oral bioavailability is poor (~20%)

Suppressive vs Episodic Therapy

• Episodic therapy: Initiated within 24 hours of prodrome - shortens duration/severity of each episode
• Suppressive/prophylactic therapy: Daily antiviral for patients with frequent recurrences (>6/year) or to reduce transmission to seronegative partners

Topical Acyclovir

• Modest benefit only for herpes labialis; not recommended for genital herpes

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11. COMPLICATIONS

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12. PREVENTION

• Safe sex practices (condoms) reduce but do not eliminate HSV-2 transmission (as virus sheds from unprotected skin)
• Suppressive antiviral therapy in an infected partner reduces transmission by ~50%
• Neonatal herpes prevention: Cesarean delivery when active genital lesions at time of labor; suppressive valacyclovir from 36 weeks in women with recurrent genital herpes
• No licensed vaccine is currently available; GEN-003 (therapeutic vaccine) is under investigation
• Pritelivir (helicase-primase inhibitor): Under investigation; reduces shedding and lesion days without requiring thymidine kinase activation (effective against TK-deficient resistant strains)

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13. SUMMARY TABLE FOR QUICK REVISION

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KEY MNEMONICS FOR EXAM

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• Fitzpatrick's Dermatology, 9e, Chapter 164 (Jeffrey I. Cohen)
• Andrews' Diseases of the Skin, 13e, Chapter 19
• Dermatology 2-Volume Set 5e (Elsevier), Chapters 78 & 80
• Cummings Otolaryngology Head and Neck Surgery, Chapter 87
• Washington Manual of Medical Therapeutics